Eosinophilic esophagitis (EE) is an emerging worldwide disease characterized by the accumulation of eosinophils in the esophagus. EE is accompanied by symptoms that frequently mimic gastroesophageal reflux disease (GERD), but EE is differentiated from GERD based on the magnitude of mucosal eosinophilia, the more severe degree of esophageal epithelial hyperplasia, and the lack of response to acid suppression therapy. In addition, EE exhibits a strong familial pattern. At present, despite the rising incidence of EE, there is a paucity of information concerning the basic causes and mechanisms of the disease. This R21 grant application, which focuses on characterizing the genetic elements of EE, fits within the mission of the NIDDK aimed to improve understanding of gastrointestinal disorders, especially since EE represents an emerging unmet medical need. Our long- term goal is to elucidate the genetic factors contributing to the susceptibility and pathogenesis of EE and other eosinophil associated gastrointestinal disorders. The objective of the proposed project is to use a candidate gene approach to detect the genes associated with EE; the candidate genes will be selected based on global gene expression profile analysis and by their potential roles in pathways germaine to EE. Specifically, we will focus on two genes, eotaxin-3 and cadherin-like 26 in the proposed study. Specific Aim 1 Test the association of the eotaxin-3 gene with EE. Eotaxin-3 is the most over-expressed gene in patients with EE (53-fold increase) compared with controls. Eotaxin-3 is a potent eosinophil chemoattractant and activating factor, providing additional rationale for examining the association of this gene with EE. Specific Aim 2: Test the association of the cadherin-like 26 gene with EE, and examine the gene-gene interaction between eotaxin-3 and cadherin-like 26 underlying susceptibility to EE. Cadherin- like 26 is another gene markedly over-expressed in EE patients (23-fold increase compared with controls). It belongs to the cadherin superfamily which has been reported to be associated with a variety of inflammatory and epithelial proliferation diseases. EE is associated with marked expansion of basal layer thickness. It has been demonstrated by part of our research team that the increased thickness of the basal layer correlated with the increased epithelial cell proliferation. Therefore, the results obtained from the proposed study will provide valuable insight into the pathogenesis of EE. Both population and family based approaches will be conducted to test the association of these two genes with EE, respectively. Then the analyses will be stratified by several clinical parameters (atopic status, age of onset, disease severity, and gender). It is anticipated that uncovering the genetic elements underlying EE will dramatically improve the understanding and management of EE by providing important diagnostic and prognostic information and also by providing insight that may lead to more effective therapeutic strategies. [unreadable] [unreadable]